A new study has revealed crucial information on bacteria's
coping strategies, paving the way for novel approaches to tackle
infection.
For over 40 years, scientists have known that when bacteria are
under stress they produce a molecule called guanosine
tetraphosphate (ppGpp) that allows them to survive in difficult
conditions and even resist the action of antibiotics. This molecule
triggers a pattern of genetic activity, switching on and off the
appropriate genes that instruct the bacteria to stop growing and
use minimal resources. Until now, the control mechanisms that
allowed bacteria to accumulate ppGpp have remained something of a
mystery but a new study by researchers from Imperial College London
has shed light on this important area.
The discovery came about when researchers put the ubiquitous
Escherichia coli (E. coli) bacteria under stress by starving the
bugs of nitrogen, which is essential for growth. They discovered
that a gene control protein called NtrC plays a central role in the
process that controls the levels of the ppGpp molecule, which in
turn triggers bacteria's coping strategies.
When bacteria are stressed they 'lie low' and minimise their
activity. Antibiotics target bacteria by sensing their activity so
when bacteria are in 'coping mode' the drugs can no longer detect
targets in the bacteria and take effect. Chronic or long-lasting
infections are often caused by bacteria applying these efficient
coping strategies and 'going into hiding'. If scientists can find
ways to block this coping mechanism, then bacteria will remain
exposed and vulnerable so antibiotics can target them
effectively.
"It was a revelation," said lead author Professor Sivaramesh
Wigneshweraraj from Imperial College London. "We have known for a
long time that when bacteria run out of nutrients they adapt to the
situation through the release of ppGpp. So we knew the cause and
the effect but we didn't know what happened in between. Now we have
shone a light into the engine room of bacteria's coping mechanism
by discovering that the protein NtrC plays an essential role in how
bacteria cope under conditions of nitrogen starvation. This is a
hugely important finding for the fundamental biology of bacteria
and could have significant practical implications in terms of
improving and developing drugs to fight bacterial infections."
When bacteria are under stress of any type, they respond by
switching on the relA gene, which then produces ppGpp. This
molecule acts as a 'messenger' triggering a pattern of genetic
activity to produce an effective coping strategy. When the research
team were investigating the NtrC protein, which is a well-known
master gene regulator that allows bacteria to cope with nitrogen
starvation, they unexpectedly discovered that NtrC bound to a site
close to the relA gene. They then demonstrated that NtrC is the
trigger that switches on the relA gene, which allows ppGpp to start
the coping process.
Dr Daniel Brown, a postdoctoral research fellow at Imperial
College London, said: "This shows that bacteria have a very
efficient way to cope with starvation for nutrients: they use the
same gene control protein NtrC to simultaneously turn on genes that
allow them to scavenge for new nitrogen sources and to activate a
response that promotes longer-term survival. This gives them the
best chance of survival while the status of their environment is
uncertain. It seems as though they are hedging their bets,
something that we may be able to exploit from further study."
The paper, Nitrogen stress response and stringent response are coupled in
Escherichia coli, is published in Nature
Communications.